It is now being recognized that the pathological consequences of many immune system mediated diseases including endotoxin induced septic shock (1), arthritis (2), psoriasis (3), multiple sclerosis (4), allergic asthma (5), metastatic melanoma (6) and as well as graft rejection (7) is the result of endothelial cell leukocyte attachment mediated by the adhesion molecules (8). Adhesion molecules expressed on the surface of endothelial lining of the blood vessels allow leukocyte attachment and trafficking to the site of inflammation. Cytokines like TNF-xcex1 produced by macrophages in response to inflammatory stimuli, induce expression of adhesion molecules (ICAM/VCAM) on the endothelial cell surface. As a result, activated lymphocytes, monocytes, or neutrophils bearing the ligand for adhesion molecules adhere to the endothelial cells and cause damage to the vascular lining and the surrounding tissue due to release of free radicals and other lytic molecules. An agent that blocks the expression of adhesion molecules at the site of inflammation in response to any inflammatory stimuli may therefore prevent endothelialxe2x80x94leukocyte attachment and consequently may have preventive and/or therapeutic effects in clinical situation of septic shock, arthritis, psoriasis, multiple sclerosis, allergic asthma, metastatic melanoma and graft rejection. It has been discovered that berberine or its pharmaceutically acceptable salts block adhesion of molecules to endothelial cell surface.
Berberine may be isolated from Berberis airistata. Berberis aristata has been widely used in traditional Indian medicine for treatment of gastroenteritis, and skin and eye infections (Chopra et al., 1956; Nadkarni 1954). The chemistry and pharmacological effects of protoberberine alkaloids have been described in the scientific literature. Berberine has been reported to have direct anti-bacterial (Sado, 1947; Dutta and Panse, 1962), anti-amoebic (Subbaihah and Amin, 1967; Dutta and Iyer, 1968) and anti-leishmanial effects (Dasgupta and Dikshit, 1929; Steck, 1974; Ghosh et al., 1983, 1985) and cytotoxic effects against certain types of tumor cells (for review see Bhakuni and Jain 1986). Berberine has been shown to complex with DNA (Krey and Hahn 1969; Maitia and Chowdhuri, 1981) and is being used as a specific stain for mast cells because of its specificity of binding with herapin (Berlin and Enerback, 1983, 1984).
Japanese Patent 07-316051 published Dec. 5, 1995 (Kangegafuchi Chemical Co. Ltd.) discusses the use of berberine or its pharmacologically tolerable salt as an immunosuppressant specifically for autoimmune diseases such as rheumatism and for treatment of allergies and to prevent rejection of isografts. This reference discloses that berberine inhibits antibody production by B cells, suppresses humoral immunity and has no effect on propagation of T cells.
This invention describes a method for blocking the attachment of leukocytes to endothelial cells/lining of the blood vessels using a plant derived protoberberine alkaloid, berberine or its pharmaceutically acceptable salts.
An object of this invention is to inhibit the attachment of leukocytes to the endothelial cells/lining of the blood vessel due to inhibition of cytokine induced expression of adhesion molecules on the endothelial cells.
A further object of this invention relates to prevention of tissue damage by inhibiting the attachment of leukocytes to the endothelial cells/lining of the blood vessels.
Yet another object of this invention is a method for prevention and/or treatment of clinical manifestations that involve endothelial cell-leukocyte attachment, for example septic shock, arthritis, psoriasis, multiple sclerosis, allergic asthma, metastatic melanoma and graft rejection.